Immune diseases mean diseases in which the components of an immune system cause, mediate, or contribute pathological conditions, and particularly, inflammatory disorder is one of the most important health problems around the world. Inflammation generally means a localized protective response of body tissues against the host intrusion by foreign substances or harmful stimuli. The cause of inflammation includes infectious causes such as bacteria, viruses, and parasites; physical causes such as burns or radiation; chemicals such as toxins, drugs, or industrial agents; immune responses such as allergy and autoimmune responses, conditions associated with oxidative stress, or the like.
The inflammation is characterized by symptoms such as pain, a red phenomenon, swelling, heat, and an eventual functional loss of an infected area. These symptoms are results of a series of complex interactions occurred between cells in the immune system. Due to the cell reaction, as a result, an interaction network of various groups of inflammatory mediators [proteins (for example, cytokines, enzymes (e.g., protease, peroxidase), major basic proteins, adhesive molecules (ICAM, VCAM), lipid mediators (e.g., eicosanoid, prostaglandin, leukotriene, platelet activating factors (PAF)), reactive oxygen species (e.g., hydroperoxide, superoxide anion O2-, nitric oxide (NO), etc)] is generated. However, most of the mediators are also normal cell activity regulators. Accordingly, while the host is not controlled due to the lack of the inflammatory response, the host is damaged (that is, infected), and therefore, due to the chronic inflammation, partially, some of the aforementioned mediators are excessively generated and thus, the mediated inflammatory diseases are caused.
Further, an autoimmune disease which is one of the immune diseases has a feature that the immune system causes a spontaneous response by attacking its organ. The responses are caused by recognition of auto-antigen by the T lymphocytes and thus humoral (generation of auto-antigens) and cellular (an increase in cytotoxicity activity of lymphocytes and macrophages) immune responses are caused. The autoimmune diseases include rheumatic diseases, psoriasis, systemic dermatomyositis, multiple sclerosis, lupus erythematosus, deterioration of immune responses by antigens, i.e., asthma, drug or food allergies, or the like. The diseases are limitative and chronic diseases, and in some cases become fatal. The effective treating method capable of treating the diseases until now is not present. Therefore, drugs, medicines, or media capable of reducing or alleviating the diseases in the progress of the disease may become an important solution means for a patient's health.
Concentrated efforts to find appropriate drugs and methods by searching methods for treating the autoimmune diseases have been made. Today, the treatment of autoimmune diseases is mainly based on the use of immunosuppressive drugs, for example, glucocorticoids, calcineurin inhibitors, and antiproliferative-anti metabolites. However, these drugs act on a variety of targets, thereby entirely decreasing the immune function. Further, in the case of using the pharmacotherapies for a long time, various cytotoxic effects may be shown and the immune system is non-specifically suppressed to cause infection or cancers of patients. Calcineurin and glucocorticoid have another problem due to their nephrotoxicity and diabetes induced characteristics, and thus in the case of some of clinical symptoms (e.g., renal insufficiency, diabetes, etc.), the use thereof is restricted.
Accordingly, as a substance capable of treating immune diseases such as autoimmune diseases and inflammatory diseases, development of novel immune diseases therapeutic agents having an excellent treating effect without side effects is required.
As a result, the inventors synthesized various kinds of biguanide derivative compounds and verified these activities while finding materials with fewer human side effects capable of effectively preventing or treating immune diseases or inflammatory diseases and thus verified effects of inhibiting generation of IL-17 and TNF-α as inflammatory cytokines, increasing activity of regulatory T cells having an immunomodulatory function, and having a therapeutic effect in vivo in the case of applying the biguanide derivative compound of the present invention to an inflammatory bowel disease animal model and an acute graft versus host disease animal model, and completed the present invention.